U.S. Pat. No. 5,039,802, awarded to T. J. Blacklock, T. K. Jones, D. J. Mathre and L. C. Xavier, discloses that tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole--b orane (1) is a stable, free flowing, crystalline solid. In contrast, .beta.-methyl oxazaborolidine (2) is extremely sensitive to the presence of moisture. Both the (R) and (S) enantiomers of 1 have been utilized as enantioselective catalysts for the reduction of prochiral ketones. The yield and enantioselectivity of reductions using catalytic amounts 1 are identical to those using freshly prepared toluene solutions of 2. When used stoichiometrically (0.5 mol 1 per mol of ketone) the enantioselectivity is superior to the catalytic procedure. In this patent application we identify the parameters necessary to maximize the isolated yield of 1. ##STR1##
A detailed synthesis of .beta.-methyl oxazaborolidine 2 has been described in above-mentioned U.S. Pat. No. 5,039,802. The protocol described in this patent involved addition of 0.667 mol of trimethylboroxine (4) to diphenylprolinol (3) in dry toluene, aging for 0.5 hour at 20.degree.-25.degree. C., and then heating to reflux for 1-2 hours. This was followed by subsequent additions of toluene and concentrations (Scheme 1). Although this procedure works well on a small scale (especially when using a Dean-Stark trap for removal of water) we began to encounter problems driving the reaction to completion on a larger scale. Indeed, we found the 1-2 hour age at reflux to be unnecessary, and may in fact be deleterious for the clean production of oxazaborolidine 2.
Heating intermediate 5 produces oxazaborolidine 2 and methylboronic acid. Under these same conditions methylboronic acid is converted to trimethylboroxine and water, which co-distill with the toluene. Removal of trimethylboroxine and water drives the reaction to completion. Water can also react with oxazaborolidine 2 to afford the unstable water adduct 6 which quickly disproportionates to intermediate 5 and diphenylprolinol 3 (Scheme 2). The 1-2 hour at reflux (without efficient removal of water) provides an opportunity for water to react with the oxazaborolidine. This becomes a more significant problem at larger scales when the time required to heat the mixture to reflux increases. Simply removing the 1-2 hour age at reflux from the process minimizes this problem. We disclosed this modification in our copending U.S. patent application Ser. No. 730,316 filed Jul. 15, 1991. ##STR2## In addition, one can easily recover a batch containing residual diphenylprolinol, intermediate 5, or water adduct 6. This is achieved by addition of a second charge of trimethylboroxine (5-10 mol %) followed by a toluene flush. The ability to recover (or regenerate) a batch in this manner provides an important safety net, especially when large quantities of the oxazaborolidine are involved. ##STR3##
The original procedure to prepare oxazaborolidine--borane complex 1 disclosed in U.S. Pat. No. 5,039,802 involved addition of 2 mol of borane-dimethyl sulfide (BMS) to a toluene solution of oxazaborolidine 2. Removal of dimethyl sulfide using a nitrogen sweep drives the equilibrium, and at an undefined point the product would crystallize (Scheme 3). Larger batches required longer times to remove the foul smelling dimethyl sulfide. An additional concern when using a nitrogen sweep is the loss of free borane. This makes accurate charging of the BMS difficult. ##STR4##